Abstract
Bipolar disorder is a severe mental illness characterized by recurrent episodes of mania and depression affecting about 1% of the population. The pathophysiology of this illness is unclear. Strong effects of genetic factors have been evidenced by family, twin, and linkage studies. The mood stabilizers such as valproate, lithium and carbamazepine, are effective for this illness. We have recently reported that XBP1, a pivotal gene in endoplasmic reticulum stress response, is one of key genes associated with this illness (Kakiuchi et al, Nature Genetics, 2003). Using DNA microarray analysis of lymphoblastoid cells derived from two pairs of monozygotic twins discordant for the disorder, we found down-regulated expression of ER stress response-related genes in both the affected twins. A polymorphism (Rs2269577, C to G) in the promoter region of XBP1, losing the putative XBP1 binding site, was associated with this illness by genetic analyses. XBP1-dependent transcription activity of the G allele, the risk allele for bipolar disorder, was lower than that of the C allele, and in the cells having G allele, induction of XBP1 expression upon ER stress with thapsigargin was remarkably reduced. Valproate rescued the impaired ER stress response by inducing ATF6, the upstream gene of XBP1. Our results suggest a pathophysiological role of ER stress response pathway, especially the signaling involving XBP1 gene, in bipolar disorder. Even the function of XBP1 and ER stress response pathway in normal brain has not been clarified yet and it would be a good theme for understanding the pathophysiology of this illness from new aspect. [Jpn J Physiol 54 Suppl:S40 (2004)]
